JP2008535871A - 5-Methyl-1- (substituted phenyl) -2- (1H) -pyridone in the manufacture of a medicament for treating fibrosis in an organ or tissue - Google Patents
5-Methyl-1- (substituted phenyl) -2- (1H) -pyridone in the manufacture of a medicament for treating fibrosis in an organ or tissue Download PDFInfo
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- JP2008535871A JP2008535871A JP2008505716A JP2008505716A JP2008535871A JP 2008535871 A JP2008535871 A JP 2008535871A JP 2008505716 A JP2008505716 A JP 2008505716A JP 2008505716 A JP2008505716 A JP 2008505716A JP 2008535871 A JP2008535871 A JP 2008535871A
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- methyl
- pyridone
- fibrosis
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Abstract
器官又は組織における線維症を処置するための医薬の製造における5−メチル−1−(置換されたフェニル)−2−(1H)−ピリドンの使用。それは、5−メチル−1−(置換されたフェニル)−2−(1H)−ピリドンが、様々なECMによって生産された細胞を阻害することができると共にそれらの効果がピルフェニドンよりも高いものであることを示唆する。従って、このタイプの化合物を、器官及び組織において抗繊維化剤を調製するための活性な成分として使用することができる。 Use of 5-methyl-1- (substituted phenyl) -2- (1H) -pyridone in the manufacture of a medicament for treating fibrosis in an organ or tissue. It is that 5-methyl-1- (substituted phenyl) -2- (1H) -pyridone can inhibit cells produced by various ECMs and their effects are higher than pirfenidone. I suggest that. Therefore, this type of compound can be used as an active ingredient for preparing antifibrotic agents in organs and tissues.
Description
本発明は、5−メチル−1−(置換されたフェニル)−2−(1H)−ピリドン類の使用に関係する。より詳しくは、本発明は、器官又は組織における線維症を処置するための医薬の製造における5−メチル−1−(置換されたフェニル)−2−(1H)−ピリドン類の使用に関係する。 The present invention relates to the use of 5-methyl-1- (substituted phenyl) -2- (1H) -pyridones. More particularly, the present invention relates to the use of 5-methyl-1- (substituted phenyl) -2- (1H) -pyridones in the manufacture of a medicament for treating fibrosis in an organ or tissue.
線維症は、様々な器官又は組織において起こり得るが、いずれの器官又は組織の内の健康な細胞の低減及び繊維化の結合性の組織の質量における増加をも引き起こすと共に、ついには、器官又は組織の正常な構造を損傷させる。損傷は、影響を及ぼされた器官又は組織の生理学的な及び生化学的な機能を減損し得ると共に、器官が完全に活動停止させられることを引き起こすこともある。器官及び組織の線維症についての病原論、診断の方法、予防及び処置の方法は、広範に研究されてきたものである。大幅な進歩は、ある一定のエリアにおいてなされてきたものである。しかしながら、特に有効な治療法のものを開発するというエリアにおいて、なお多数の挑戦がある。 Fibrosis can occur in a variety of organs or tissues, but also causes a decrease in healthy cells and an increase in the mass of fibrotic connective tissue within any organ or tissue, and eventually organs or tissues Damage the normal structure of the. Damage can impair the physiological and biochemical functions of the affected organ or tissue, and can also cause the organ to be completely deactivated. The pathogenesis, diagnostic methods, prevention and treatment methods for organ and tissue fibrosis have been extensively studied. Significant progress has been made in certain areas. However, there are still many challenges in the area of developing particularly effective treatments.
器官又は組織の線維症が、柔組織の細胞の炎症性の変性及び昏睡を引き起こすものである、炎症、免疫学的な反応、虚血、血液力学の変化などのような多重の因子によって引き起こされることは、一般に信じられることである。減損した柔組織の細胞は、次には、数多くのサイトカイン類及び成長因子を解放するためにマクロファージを活性化させるが、それらの間で、TGF−βが、決定的なものである。TGF−βは、細胞を生産する静止状態の細胞外の基質(ECM)を活性化すると共にそれらを筋繊維芽細胞の中へ戻すことができる。新しく形成された筋繊維芽細胞は、コラーゲン、ECMの鍵となるタンパク質の生産を増加させるだけでなく、ECMの破壊をもまた減少させる。正味の結果は、器官又は組織の線維症に至るものである、細胞外の基質の累積である。このように、器官又は組織の線維症の発症及び発達は、炎症性の応答の結果及び炎症性のサイトカイン類、主としてTGF−βの生産である。ECMの累積並びに器官及び組織の線維症の形成におけるTGF−βの重大な役割のおかげで、論理的に、抗繊維化の薬物の早期の発達における重要な目標の一つは、化合物を調査することであるが、それは、炎症前のサイトカイン、TGF−βの生産を阻害することができるものである。しかしながら、いずれの抗繊維化の薬物の候補についても、より確信するデータは、明白に、様々な生体内の繊維化のモデルを使用する試験から来ることになる。 Organ or tissue fibrosis is caused by multiple factors such as inflammation, immunological reactions, ischemia, hemodynamic changes, etc. that cause inflammatory degeneration and coma of parenchyma cells That is generally believed. Impaired parenchyma cells in turn activate macrophages to release numerous cytokines and growth factors, among which TGF-β is critical. TGF-β can activate quiescent extracellular matrix (ECM) that produces cells and return them into myofibroblasts. Newly formed myofibroblasts not only increase the production of collagen, a key protein of ECM, but also reduce the destruction of ECM. The net result is the accumulation of extracellular matrix that leads to organ or tissue fibrosis. Thus, the onset and development of organ or tissue fibrosis is the result of an inflammatory response and the production of inflammatory cytokines, primarily TGF-β. Thanks to the critical role of TGF-β in the accumulation of ECM and the formation of organ and tissue fibrosis, logically, one of the important goals in the early development of antifibrotic drugs is to investigate compounds In fact, it is capable of inhibiting the production of a pre-inflammatory cytokine, TGF-β. However, more confident data for any antifibrotic drug candidate will obviously come from trials using various in vivo fibrosis models.
抗炎症及び抗繊維化の活性を呈示するものである、多くの化合物は、記載されてきたものである。米国特許第3,839,346号明細書(特許文献1)、米国特許第3,974,281号明細書(特許文献2)、米国特許第4,042,699号明細書(特許文献3)、及び米国特許第4,052,509号明細書(特許文献4)は、後に続くピリドン様の式(O): Many compounds have been described that exhibit anti-inflammatory and anti-fibrotic activity. US Pat. No. 3,839,346 (Patent Document 1), US Pat. No. 3,974,281 (Patent Document 2), US Pat. No. 4,042,699 (Patent Document 3) , And U.S. Pat. No. 4,052,509, which is followed by a pyridone-like formula (O):
を備えた合計で29個の化合物を公表したが、そこでは、Aは、芳香族の基である。これらの化合物は、良好な抗炎症及び鎮痛性の活性を有すると共に、尿酸及びブドウ糖の血清のレベルを低減することができる。一つの化合物、特に5−メチル−1−フェニル−2(1H)−ピリドンは、最良の活性及び低い毒性を有する。
A total of 29 compounds were published, where A is an aromatic group. These compounds have good anti-inflammatory and analgesic activity and can reduce uric acid and glucose serum levels. One compound, particularly 5-methyl-1-phenyl-2 (1H) -pyridone, has the best activity and low toxicity.
米国特許第5,518,729号明細書(特許文献5)及び米国特許第5,716,632号明細書(特許文献6)が、抗繊維化の活性をN−置換された2(1H)−ピリドン(I)又はN−置換された3(1H)−ピリドンのいずれかの追加の44個の化合物まで拡張するが、欧州特許出願公開第1138329号明細書(特許文献7)は、有効な抗繊維化の化合物:ピルフェニドン(PFD,5−メチル−10−フェニル−2(1H)−ピリドン)を記載した。 US Pat. No. 5,518,729 (Patent Document 5) and US Pat. No. 5,716,632 (Patent Document 6) have N-substituted 2 (1H) anti-fibrotic activity. Although it extends to an additional 44 compounds of either pyridone (I) or N-substituted 3 (1H) -pyridone, EP 1138329 is effective. Antifibrotic compound: Pirfenidone (PFD, 5-methyl-10-phenyl-2 (1H) -pyridone) was described.
5−メチル−1−フェニル−2(1H)−ピリドン(ピルフェニドン,PFD)の抗繊維化の活性の効能は、様々な動物のモデル及び人間の臨床的な試行においてさらに立証されてきた(Shimazu et al.,ピルフェニドンは、部分的な腎臓切除を伴ったラットにおける残存物の腎臓におけるコラーゲンの累積を予防する。Kidney Int.52(Supple 63):S239−243(1997)(非特許文献1);Raghu et al.,新しい抗繊維化剤、ピルフェニドンでの特発性の肺の線維症の処置。Am.J.Respir.Crit.Care Med.159:1061−1069 (1999)(非特許文献2))ものである。これらの研究は、ピルフェニドンが、予防するだけでなく、過剰な細胞外の基質の累積を逆転させることをもまた示唆した。ピルフェニドンの薬理学的な機構は、まだ十分に理解されてきたものではないが、しかし、データは、今まで、ピルフェニドンが、(TGF−βを含む)サイトカイン類を下方制御することに有効な化合物であると共に、多重の因子を規制することを通じて繊維芽細胞の活性を減少させることを示唆する。 The efficacy of the anti-fibrotic activity of 5-methyl-1-phenyl-2 (1H) -pyridone (pirfenidone, PFD) has been further demonstrated in various animal models and human clinical trials (Shimazu et al. al., pirfenidone prevents residual collagen accumulation in the kidney in rats with partial nephrectomy Kidney Int. 52 (Supple 63): S239-243 (1997); Raghu et al., Treatment of Idiopathic Pulmonary Fibrosis with a New Antifibrotic Agent, Pirfenidone, Am.J.Respir.Crit.Care Med.159: 1061-1069 (1999)) Is. These studies also suggested that pirfenidone not only prevents but also reverses the accumulation of excess extracellular matrix. The pharmacological mechanism of pirfenidone has not yet been fully understood, but the data has so far shown that pirfenidone is an effective compound for downregulating cytokines (including TGF-β). And suggests reducing fibroblast activity through the regulation of multiple factors.
中国特許第02114190.8号は、後に続く一般的な構造の式(I): Chinese Patent No. 02114190.8 is the general structure formula (I) that follows:
を有する、合計38個の新しい5−メチル−1−(置換されたフェニル)−2(1H)−ピリドン化合物の識別及び合成を記載した。
The identification and synthesis of a total of 38 new 5-methyl-1- (substituted phenyl) -2 (1H) -pyridone compounds having
n=1である場合には、置換Rは、F、Br、Iであることができる。n=2である場合には、置換Rは、F、Cl、Br、I、アルキル、アルコキシ、ハロゲン化されたアルキル基であることができる。R基についての相対的な位置は、オルト又はメタ又はパラである。 When n = 1, the substitution R can be F, Br, I. When n = 2, the substitution R can be F, Cl, Br, I, alkyl, alkoxy, halogenated alkyl group. The relative position for the R group is ortho or meta or para.
米国特許第5,716,632号明細書は、米国特許第3,974,281号明細書におけるGadekarによって当初より記載された5−メチル−1−(置換されたフェニル)−2(1H)−ピリドンの6個の構造の式を列挙した。これらの“置換されたフェニル”化合物について、Gadekarは、最良の生物学的な活性を備えた化合物として置換されてないフェニルを教示するものである構造−活性な関係を確立した。しかしながら、5−メチル−1−(置換されたフェニル)−2(1H)−ピリドン、1−(3’−フルオロフェニル)−5−メチル−2(1H)−ピリドンが、試験管内である一定の生物学的な活性を示したことは、報告されてきたものである(J.Cent.South Univ.Med.Sci.29:139(2004))。このように、構造の式IIを有する置換されたフェニル化合物が、いずれの望ましい抗繊維化の活性をも有するのであろうかどうかを決定することは、関心のあることである。
前述の背景技術に基づいて、本発明は、ピリドン化合物の新規な群を公表するが、それらを、器官又は組織の線維症の予防及び処置用の抗繊維化の薬物の調製に使用することができる。 Based on the foregoing background art, the present invention publishes a new group of pyridone compounds, which can be used in the preparation of antifibrotic drugs for the prevention and treatment of organ or tissue fibrosis. it can.
本発明は、新規な群のピリドン化合物について一般的な構造の式(I): The present invention provides a general structure of formula (I) for a novel group of pyridone compounds:
を提供する。
I will provide a.
n=1の場合には、置換Rは、F、Cl、Br、I、ニトロ、アルキル、アルコキシ、ハロゲン化されたアルキルの基であることができる;n=2の場合には、置換Rは、F、Cl、Br、I、アルキル、アルコキシ、ハロゲン化されたアルキルの基であることができる。これらの化合物を、薬物の調製に使用することができると共に、それは、幅広い一連の範囲の抗器官線維症又は抗組織線維症を有するものである。 When n = 1, the substitution R can be F, Cl, Br, I, nitro, alkyl, alkoxy, halogenated alkyl group; when n = 2, the substitution R is , F, Cl, Br, I, alkyl, alkoxy, halogenated alkyl groups. These compounds can be used in the preparation of drugs and have a wide range of anti-organ fibrosis or anti-tissue fibrosis.
本発明において、用語“抗器官又は組織線維症”は、器官/組織における線維症を予防すること、又は、器官/組織における繊維化の工程を遅くする若しくは停止させることを、及び/又は、器官/組織における繊維化の健康状態を逆転することを、意味する。 In the present invention, the term “anti-organ or tissue fibrosis” refers to preventing fibrosis in an organ / tissue, or slowing or stopping the process of fibrosis in an organ / tissue, and / or organ / Reverses the health status of fibrosis in the tissue.
構造式(I)においては、好適なnの数は、1であると共に好適なRは、F、Br、Iである。 In the structural formula (I), the preferable number of n is 1 and preferable R is F, Br, or I.
n=2の場合には、Rは、F、Cl、Br、I、飽和の直鎖のアルキル基、飽和の直鎖のアルコキシ基、飽和の直鎖のハロゲン化されたアルキル基であることができる。R基についての相対的な位置は、オルト又はメタ又はパラである。 When n = 2, R may be F, Cl, Br, I, a saturated linear alkyl group, a saturated linear alkoxy group, a saturated linear halogenated alkyl group. it can. The relative position for the R group is ortho or meta or para.
Fについての好適な位置は、メタの位置、即ち、3’−フルオロフェニルである。 The preferred position for F is the meta position, ie 3'-fluorophenyl.
本発明におけるアルキル置換基は、1−6個の炭素を備えた飽和の直鎖の又は分岐のもののいずれかであると共に、好適なものは、1−4個の炭素である。 The alkyl substituents in the present invention are either saturated linear or branched with 1-6 carbons, and preferred are 1-4 carbons.
5−メチル−1−(置換された フェニル)−2(1H)−ピリドン(構造の式I)の他の例は、後に続く化合物:を含むが、しかし、それらに限定されるものではない。 Other examples of 5-methyl-1- (substituted phenyl) -2 (1H) -pyridone (Structure Formula I) include, but are not limited to, the following compounds:
n=1,R=Brのとき、化合物は、1−(2−ブロモフェニル)−5−メチル−2−(1H)−ピリドン、1−(3−ブロモフェニル)−5−メチル−2−(1H)−ピリドン、1−(4−ブロモフェニル)−5−メチル−2−(1H)−ピリドンであることができる。 When n = 1 and R = Br, the compound is 1- (2-bromophenyl) -5-methyl-2- (1H) -pyridone, 1- (3-bromophenyl) -5-methyl-2- ( 1H) -pyridone, 1- (4-bromophenyl) -5-methyl-2- (1H) -pyridone.
n=1,R=Fのとき、化合物は、1−(2−フルオロフェニル)−5−メチル−2−(1H)−ピリドン、1−(3−フルオロフェニル)−5−メチル−2−(1H)−ピリドン、1−(4−フルオロフェニル)−5−メチル−2−(1H)−ピリドンであることができる。 When n = 1 and R = F, the compound is 1- (2-fluorophenyl) -5-methyl-2- (1H) -pyridone, 1- (3-fluorophenyl) -5-methyl-2- ( 1H) -pyridone, 1- (4-fluorophenyl) -5-methyl-2- (1H) -pyridone.
n=1,R=Iのとき、化合物は、1−(2−ヨードフェニル)−5−メチル−2−(1H)−ピリドン、1−(3−ヨードフェニル)−5−メチル−2−(1H)−ピリドン、1−(4−ヨードフェニル)−5−メチル−2−(1H)−ピリドンできる。 When n = 1 and R = I, the compound is 1- (2-iodophenyl) -5-methyl-2- (1H) -pyridone, 1- (3-iodophenyl) -5-methyl-2- ( 1H) -pyridone, 1- (4-iodophenyl) -5-methyl-2- (1H) -pyridone.
n=2,R=F、Br、又はBrのとき、化合物は、1−(2,3−ジブロモフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,4−ジブロモフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,5−ジブロモフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,6−ジブロモフェニル)−5−メチル−2−(1H)−ピリドン、1−(3,4−ジブロモフェニル)−5−メチル−2−(1H)−ピリドン、1−(3,5−ジブロモフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,3−ジクロロフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,4−ジクロロフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,5−ジクロロフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,6−ジクロロフェニル)−5−メチル−2−(1H)−ピリドン、1−(3,5−ジクロロフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,3−ジフルオロフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,4−ジフルオロフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,5−ジフルオロフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,6−ジフルオロフェニル)−5−メチル−2−(1H)−ピリドン、1−(3,5−ジフルオロフェニル)−5−メチル−2−(1H)−ピリドンであることができる。 When n = 2, R = F, Br, or Br, the compound is 1- (2,3-dibromophenyl) -5-methyl-2- (1H) -pyridone, 1- (2,4-dibromophenyl) ) -5-methyl-2- (1H) -pyridone, 1- (2,5-dibromophenyl) -5-methyl-2- (1H) -pyridone, 1- (2,6-dibromophenyl) -5 Methyl-2- (1H) -pyridone, 1- (3,4-dibromophenyl) -5-methyl-2- (1H) -pyridone, 1- (3,5-dibromophenyl) -5-methyl-2- (1H) -pyridone, 1- (2,3-dichlorophenyl) -5-methyl-2- (1H) -pyridone, 1- (2,4-dichlorophenyl) -5-methyl-2- (1H) -pyridone, 1- (2,5-dichlorophenyl) -5-methyl-2- (1H) Pyridone, 1- (2,6-dichlorophenyl) -5-methyl-2- (1H) -pyridone, 1- (3,5-dichlorophenyl) -5-methyl-2- (1H) -pyridone, 1- (2 , 3-Difluorophenyl) -5-methyl-2- (1H) -pyridone, 1- (2,4-difluorophenyl) -5-methyl-2- (1H) -pyridone, 1- (2,5-difluoro Phenyl) -5-methyl-2- (1H) -pyridone, 1- (2,6-difluorophenyl) -5-methyl-2- (1H) -pyridone, 1- (3,5-difluorophenyl) -5 -Methyl-2- (1H) -pyridone.
n=1又は2及びR=トリフルオロメチルのとき、化合物は、1−(2−トリフルオロメチルフェニル)−5−メチル−2−(1H)−ピリドン、1−(4−トリフルオロメチルフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,3−ビス−トリフルオロメチルフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,4−ビス−トリフルオロメチルフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,5−ビス−トリフルオロメチルフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,6−ビス−トリフルオロメチルフェニル)−5−メチル−2−(1H)−ピリドン、1−(3,4−ビス−トリフルオロメチルフェニル)−5−メチル−2−(1H)−ピリドン、1−(3,5−ビス−トリフルオロメチルフェニル)−5−メチル−2−(1H)−ピリドンであることができる。 When n = 1 or 2 and R = trifluoromethyl, the compound is 1- (2-trifluoromethylphenyl) -5-methyl-2- (1H) -pyridone, 1- (4-trifluoromethylphenyl) -5-methyl-2- (1H) -pyridone, 1- (2,3-bis-trifluoromethylphenyl) -5-methyl-2- (1H) -pyridone, 1- (2,4-bis-tri Fluoromethylphenyl) -5-methyl-2- (1H) -pyridone, 1- (2,5-bis-trifluoromethylphenyl) -5-methyl-2- (1H) -pyridone, 1- (2,6 -Bis-trifluoromethylphenyl) -5-methyl-2- (1H) -pyridone, 1- (3,4-bis-trifluoromethylphenyl) -5-methyl-2- (1H) -pyridone, 1- (3,5-bis-trifl B methylphenyl) -5-methyl-2-(IH) - it can be a pyridone.
n=1又は2及びR=メチルのとき、5−メチル−1−(置換されたフェニル)−2−(1H)−ピリドンは、1−(2−メチルフェニル)−5−メチル−2−(1H)ピリジン、1−(3−メチルフェニル)−5−メチル−2−(1H)ピリジン、1−(2,3−ジメチルフェニル)−5−メチル−2−(1H)ピリジン、1−(2,4−ジメチルフェニル)−5−メチル−2−(1H)ピリジン、1−(2,5−ジメチルフェニル)−5−メチル−2−(1H)ピリジン、1−(2,6−ジメチルフェニル)−5−メチル−2−(1H)ピリジン、1−(3,4−ジメチルフェニル)−5−メチル−2−(1H)ピリジン、1−(3,5−ジメチルフェニル)−5−メチル−2−(1H)ピリジン:である。 When n = 1 or 2 and R = methyl, 5-methyl-1- (substituted phenyl) -2- (1H) -pyridone is 1- (2-methylphenyl) -5-methyl-2- ( 1H) pyridine, 1- (3-methylphenyl) -5-methyl-2- (1H) pyridine, 1- (2,3-dimethylphenyl) -5-methyl-2- (1H) pyridine, 1- (2 , 4-Dimethylphenyl) -5-methyl-2- (1H) pyridine, 1- (2,5-dimethylphenyl) -5-methyl-2- (1H) pyridine, 1- (2,6-dimethylphenyl) -5-methyl-2- (1H) pyridine, 1- (3,4-dimethylphenyl) -5-methyl-2- (1H) pyridine, 1- (3,5-dimethylphenyl) -5-methyl-2 -(1H) pyridine:
n=1又は2及びR=メトキシルのとき、化合物は、1−(2−メトキシフェニル)−5−メチル−2−(1H)ピリジン、1−(3−メトキシフェニル)−5−メチル−2−(1H)ピリジン、1−(2,3−ジメトキシフェニル)−5−メチル−2−(1H)ピリジン、1−(2,4−ジメトキシフェニル)−5−メチル−2−(1H)ピリジン、1−(2,5−ジメトキシフェニル)−5−メチル−2−(1H)ピリジン、1−(2,6−ジメトキシフェニル)−5−メチル−2−(1H)ピリジン、1−(3,4−ジメトキシフェニル)−5−メチル−2−(1H)ピリジン、1−(3,5−ジメトキシフェニル)−5−メチル−2−(1H)ピリジンであることができる。 When n = 1 or 2 and R = methoxyl, the compound is 1- (2-methoxyphenyl) -5-methyl-2- (1H) pyridine, 1- (3-methoxyphenyl) -5-methyl-2- (1H) pyridine, 1- (2,3-dimethoxyphenyl) -5-methyl-2- (1H) pyridine, 1- (2,4-dimethoxyphenyl) -5-methyl-2- (1H) pyridine, 1 -(2,5-dimethoxyphenyl) -5-methyl-2- (1H) pyridine, 1- (2,6-dimethoxyphenyl) -5-methyl-2- (1H) pyridine, 1- (3,4- Dimethoxyphenyl) -5-methyl-2- (1H) pyridine, 1- (3,5-dimethoxyphenyl) -5-methyl-2- (1H) pyridine.
本発明の例に従って、好適な製薬の組成物を、抗腎性間質性線維症、抗糸球体硬化症、抗肝臓硬化症、抗肺硬化症、抗腹膜線維症、抗心筋線維症、抗皮膚線維症、抗外科的手術後付着、抗良性前立腺肥大、抗筋肉骨格線維症、抗強皮症、抗アルツハイマー病、及び、抗繊維化血管の薬物として使用することができる。 In accordance with the examples of the present invention, suitable pharmaceutical compositions are prepared as anti-renal interstitial fibrosis, anti-glomerulosclerosis, anti-liver sclerosis, anti-pulmonary sclerosis, anti-peritoneal fibrosis, anti-cardiomyopathy, It can be used as a drug for dermal fibrosis, anti-surgical post-surgical adhesion, anti-benign prostatic hypertrophy, anti-musculoskeletal fibrosis, anti-scleroderma, anti-Alzheimer's disease, and anti-fibrotic blood vessels.
また、本発明の例に従って、一般的な構造の式(I)の化合物を、住血吸虫症によって引き起こされた肝臓の線維症の処置のための治療の薬剤を調製するために使用することができる。 Also according to the examples of the present invention, the compound of formula (I) of general structure can be used to prepare a therapeutic agent for the treatment of liver fibrosis caused by schistosomiasis .
また、本発明の例に従って、一般的な構造の式(I)の化合物を、糖尿病によって引き起こされた糸球体の硬化症の処置のための治療の薬剤を調製するために使用することができる。 Also according to the examples of the present invention, compounds of formula (I) of general structure can be used to prepare therapeutic agents for the treatment of glomerular sclerosis caused by diabetes.
また、本発明の例に従って、一般的な構造の式(I)の化合物を、尿のトラックの封鎖又は糖尿病によって引き起こされた腎性の間質性の線維症の処置のための治療の薬剤を調製するために使用することができる。 Also according to an example of the present invention, a compound of formula (I) of general structure may be used as a therapeutic agent for the treatment of renal interstitial fibrosis caused by blockage of urine tracks or diabetes. Can be used to prepare.
また、本発明の例に従って、一般的な構造の式(I)の化合物からの調製された治療の薬剤を、経口的な、注射可能な、又は局所的な経路を通じて投与することができる。治療の試剤を、いずれの適当な製薬の処方にも調製することができる。 Also, according to examples of the present invention, prepared therapeutic agents from compounds of formula (I) of general structure can be administered via the oral, injectable, or topical route. The therapeutic agent can be prepared in any suitable pharmaceutical formulation.
本発明においては、選択された化合物を、細胞を生産するECM及び線維症の疾患についての様々な動物モデルを使用することで、試験してきたものである。結果は、5−メチル−1−(置換されたフェニル)−2−(1H)−ピリドン類が、細胞を生産する様々なECMを抑制することが可能なもの、及び、ピルフェニドンよりも効能のあるものであることを立証する。従って、新規な化合物のこの群を、抗器官又は組織の繊維化の薬物について活性な成分として使用することができる。 In the present invention, selected compounds have been tested using various animal models for ECM producing cells and fibrotic diseases. The results show that 5-methyl-1- (substituted phenyl) -2- (1H) -pyridones are more effective than those capable of inhibiting various ECMs that produce cells and pirfenidone. Prove that it is. Thus, this group of novel compounds can be used as active ingredients for anti-organ or tissue fibrosis drugs.
本発明において、5−メチル−1−(3’−フルオロフェニル)−2−(1H)−ピリドン(AKF−PD)は、抗繊維化の薬物の調製を例証するための例として使用されるが、それらは、5−メチル−1−(置換されたフェニル)2−(1H)−ピリドン類を含むものである。AKF−PD、5−メチル−1−(3’−フルオロフェニル)−2−(1H)−ピリドンは、中国特許第02114190.8号明細書に記載された工程に従って作られる。 In the present invention, 5-methyl-1- (3′-fluorophenyl) -2- (1H) -pyridone (AKF-PD) is used as an example to illustrate the preparation of anti-fibrotic drugs. They include 5-methyl-1- (substituted phenyl) 2- (1H) -pyridones. AKF-PD, 5-methyl-1- (3'-fluorophenyl) -2- (1H) -pyridone is made according to the process described in Chinese Patent 02114190.8.
例1
1−(3’−フルオロフェニル)−5−メチル−2−(1H)−ピリドン及びピルフェニドンによるマウスの糸球体間質の細胞の増殖の抑制
Example 1
Inhibition of proliferation of mouse glomerular stroma cells by 1- (3′-fluorophenyl) -5-methyl-2- (1H) -pyridone and pirfenidone
細胞の増殖は、MTT分析によって測定された。10%の胎児の血清を備えたDMEMは、細胞の培養物の媒質として使用された。細胞は、懸濁液において調製され(1×105/ml)、且つ、懸濁液の100μLが、96個のウェルのプレートの各々のウェルへ移された。一度細胞が、プラスチックへ付着させられると、培養物は、血清の無い媒質に変化させられ、且つ、別の24時間の間連続させられた。血清の無い媒質は、吸引され、且つ、10%の血清の媒体における様々な濃度の5−メチル−1−(3’−フルオロフェニル)−2−(1H)−ピリドン(AKD−PD)又はピルフェニドン(PFD)は、各々の濃度について5個の複製を備えた各々のウェルの中へ追加された。細胞は、12、24、及び48時間の後の薬物の処置においてMTT(ウェル当たり10μL)で染色された。4時間の温置の後に、MTTを備えた媒質は、各々のウェルから吸引された。一百μLのMTTの溶媒が、15分の間に各々のウェルへ追加された。そして、溶解させられたMTTは、570nmにおけるプレートの読取装置で測定された。 Cell proliferation was measured by MTT analysis. DMEM with 10% fetal serum was used as a medium for cell culture. Cells were prepared in suspension (1 × 10 5 / ml) and 100 μL of suspension was transferred to each well of a 96 well plate. Once the cells were attached to the plastic, the culture was changed to serum free medium and allowed to continue for another 24 hours. Serum-free medium is aspirated and various concentrations of 5-methyl-1- (3′-fluorophenyl) -2- (1H) -pyridone (AKD-PD) or pirfenidone in 10% serum medium (PFD) was added into each well with 5 replicates for each concentration. Cells were stained with MTT (10 μL per well) in drug treatment after 12, 24, and 48 hours. After 4 hours incubation, media with MTT was aspirated from each well. One hundred μL of MTT solvent was added to each well during 15 minutes. The dissolved MTT was then measured with a plate reader at 570 nm.
結果は、表1に示される。24時間で、500μg/mlのAKF−PDは、マウスの糸球体間質の細胞の増殖を抑制したが、しかし、500μg/mlのピルフェニドンは、しなかった。1000μg/ml及び2500μg/mlの濃度では、AKF−PD及びピルフェニドンの両方は、マウスの糸球体間質の細胞の増殖を抑制したが、しかし、AKF−PDは、ピルフェニドンよりも効能のあるものであった。48時間の時点で、AKF−PD及びピルフェニドンの両方は、全ての試験する濃度のレベルにおいてマウスの糸球体間質の細胞に抑制的な効果を有するものであった;しかしながら、AKF−PDは、100μg/ml、500μg/ml、1000μg/mlでピルフェニドンよりも強い効果を示した。結論において、AKF−PDは、マウスの糸球体間質の細胞の増殖を抑制することができると共にある一定の濃度のレベルでピルフェニドンよりも効能のある抑制的な効果を有する。 The results are shown in Table 1. At 24 hours, 500 μg / ml AKF-PD inhibited the growth of mouse glomerular stromal cells, but not 500 μg / ml pirfenidone. At concentrations of 1000 μg / ml and 2500 μg / ml, both AKF-PD and pirfenidone inhibited proliferation of mouse glomerular stromal cells, but AKF-PD is more effective than pirfenidone. there were. At 48 hours, both AKF-PD and pirfenidone had an inhibitory effect on mouse glomerular stromal cells at all tested concentration levels; however, AKF-PD was The effect was stronger than pirfenidone at 100 μg / ml, 500 μg / ml, and 1000 μg / ml. In conclusion, AKF-PD can suppress the proliferation of mouse glomerular stromal cells and has a more potent suppressive effect than pirfenidone at a certain concentration level.
表1
マウスの糸球体間質の細胞におけるAKF−PD及びPEDの効果
Table 1
Effects of AKF-PD and PED on cells in mouse glomerular stroma
*p<0.05 対 対照;**p<0.01 対 対照;***p<0.001対 対照
+p<0.05 対 AKF−PD;++p<0.01 対 AKF−PD;+++p<0.001 対 AKF−PD
例2
−1−(3’−フルオロフェニル)−5−メチル−2−(1H)−ピリドン及びピルフェニドンによるラットの心筋の繊維芽細胞の増殖の抑制
* P <0.05 vs control; ** p <0.01 vs control; *** p <0.001 vs control
+ P <0.05 vs AKF-PD; ++ p <0.01 vs AKF-PD; +++ p <0.001 vs AKF-PD
Example 2
Inhibition of rat myocardial fibroblast proliferation by -1- (3'-fluorophenyl) -5-methyl-2- (1H) -pyridone and pirfenidone
細胞の増殖は、MTT分析によって測定された。10%の胎児の血清を備えたDMEMは、細胞の培養物の媒質として使用された。細胞は、懸濁液において調製され(1×105/ml)、且つ、懸濁液の100μLが、96個のウェルのプレートの各々のウェルへ移された。一度細胞が、プラスチックへ付着させられると、培養物は、血清の無い媒質に変化させられ、且つ、別の24時間の間に温置させられた。そして、血清の無い媒質は、吸引され、且つ、10%の血清の媒体における様々な濃度の1−(3’−フルオロフェニル)−5−メチル−2−(1H)−ピリドン(AKD−PD)又はピルフェニドン(PFD)は、各々の濃度について5個の複製を備えた各々のウェルの中へ追加された。細胞は、12、24、又は48時間の後の薬物の処置においてMTT(ウェル当たり10μL)で染色された。4時間の温置の後に、MTTを備えた媒質は、各々のウェルから吸引された。一百μLのMTTの溶媒が、15分の間に各々のウェルへ追加され、且つ、溶解させられたMTTは、570nmにおけるプレートの読取装置で測定された。 Cell proliferation was measured by MTT analysis. DMEM with 10% fetal serum was used as a medium for cell culture. Cells were prepared in suspension (1 × 10 5 / ml) and 100 μL of suspension was transferred to each well of a 96 well plate. Once the cells were attached to the plastic, the culture was changed to serum-free medium and incubated for another 24 hours. The serum-free medium is then aspirated and various concentrations of 1- (3′-fluorophenyl) -5-methyl-2- (1H) -pyridone (AKD-PD) in 10% serum medium Or pirfenidone (PFD) was added into each well with 5 replicates for each concentration. Cells were stained with MTT (10 μL per well) in drug treatment after 12, 24, or 48 hours. After 4 hours incubation, media with MTT was aspirated from each well. One hundred μL of MTT solvent was added to each well during 15 minutes, and the dissolved MTT was measured with a plate reader at 570 nm.
結果は、表2に示される。100μg/ml、500μg/ml、1000μg/ml及び2500μg/mlの濃度で、AKF−PD及びピルフェニドンの両方は、24時間の処置の後にラットの心筋の繊維芽細胞の増殖を抑制することができる;しかしながら、1000μg/ml及び2500μg/mlのレベルで、AKF−PDは、ピルフェニドンよりも効能のあるものであった。同じ濃度の範囲で、AKF−PD及びピルフェニドンの両方は、48時間の後に細胞の増殖における抑制的な効果を示したが、しかし、AKF−PDは、100μg/ml、500μg/ml、及び1000μg/mlで、より能のあるものであった。結論において、AKF−PDは、ラットの心筋の繊維芽細胞においてピルフェニドンよりも効能のある抗増殖剤である。 The results are shown in Table 2. At concentrations of 100 μg / ml, 500 μg / ml, 1000 μg / ml and 2500 μg / ml, both AKF-PD and pirfenidone can inhibit the proliferation of rat myocardial fibroblasts after 24 hours of treatment; However, at the 1000 and 2500 μg / ml levels, AKF-PD was more potent than pirfenidone. At the same concentration range, both AKF-PD and pirfenidone showed an inhibitory effect on cell growth after 48 hours, but AKF-PD was 100 μg / ml, 500 μg / ml, and 1000 μg / ml. In ml, it was more capable. In conclusion, AKF-PD is a more potent antiproliferative agent than pirfenidone in rat myocardial fibroblasts.
表2
ラットの心筋の繊維芽細胞におけるAKF−PD及びPEDの効果
Table 2
Effects of AKF-PD and PED on rat myocardial fibroblasts
*p<0.05 対 対照;**p<0.01 対 対照;***p<0.001 対 対照
+p<0.05 対 AKF−PD;++p<0.01 対 AKF−PD;+++p<0.001 対 AKF−PD
例3
1−(3’−フルオロフェニル)−5−メチル−2−(1H)−ピリドン及びピルフェニドンによる人間の星状細胞の増殖の抑制
細胞の増殖は、MTT分析によって測定された。10%の胎児の血清を備えたDMEMは、細胞の培養物の媒質として使用された。細胞は、懸濁液において調製され(1×105/ml)、且つ、懸濁液の100μLが、96個のウェルのプレートの各々のウェルへ移された。一度細胞が、プラスチックへ付着させられると、培養物は、血清の無い媒質に変化させられ、且つ、別の24時間の間に温置させられた。そして、血清の無い媒質は、吸引され、且つ、10%の血清の媒体における様々な濃度の1−(3’−フルオロフェニル)−5−メチル−2−(1H)−ピリドン(AKD−PD)又はピルフェニドン(PFD)は、各々の濃度について5個の複製を備えた各々のウェルの中へ追加された。細胞は、12、24、又は48時間の後の薬物の処置においてMTT(ウェル当たり10μL)で染色された。4時間の温置の後に、MTTを備えた媒質は、各々のウェルから吸引された。一百μLのMTTの溶媒が、15分の間に各々のウェルへ追加され、且つ、そして、溶解させられたMTTは、570nmにおけるプレートの読取装置で測定された。
* P <0.05 vs control; ** p <0.01 vs control; *** p <0.001 vs control
+ P <0.05 vs AKF-PD; ++ p <0.01 vs AKF-PD; +++ p <0.001 vs AKF-PD
Example 3
Inhibition of human astrocyte proliferation by 1- (3′-fluorophenyl) -5-methyl-2- (1H) -pyridone and pirfenidone Cell proliferation was measured by MTT analysis. DMEM with 10% fetal serum was used as a medium for cell culture. Cells were prepared in suspension (1 × 10 5 / ml) and 100 μL of suspension was transferred to each well of a 96 well plate. Once the cells were attached to the plastic, the culture was changed to serum-free medium and incubated for another 24 hours. The serum-free medium is then aspirated and various concentrations of 1- (3′-fluorophenyl) -5-methyl-2- (1H) -pyridone (AKD-PD) in 10% serum medium Or pirfenidone (PFD) was added into each well with 5 replicates for each concentration. Cells were stained with MTT (10 μL per well) in drug treatment after 12, 24, or 48 hours. After 4 hours incubation, media with MTT was aspirated from each well. One hundred μL of MTT solvent was added to each well during 15 minutes, and the dissolved MTT was measured with a plate reader at 570 nm.
結果は、表3に示される。500μg/ml、1000μg/ml、及び2500μg/mlで、AKF−PD及びピルフェニドンの両方は、12時間の後の薬物の処置から始まる人間の星状細胞の増殖を抑制することができる。24時間の時点で、1000μg/ml及び2500μg/mlのAKF−PDは、ピルフェニドンよりも抑制的なものであった。48時間で、AKF−PDは、500μg/ml、1000μg/ml及び2500μg/mlの濃度でピルフェニドンよりも抑制的なものであった。結論において、AKF−PDは、人間の星状細胞においてピルフェニドンよりも効能のある抗増殖剤である。 The results are shown in Table 3. At 500 μg / ml, 1000 μg / ml, and 2500 μg / ml, both AKF-PD and pirfenidone can inhibit the growth of human astrocytes starting with drug treatment after 12 hours. At 24 hours, 1000 μg / ml and 2500 μg / ml AKF-PD were more inhibitory than pirfenidone. At 48 hours, AKF-PD was more inhibitory than pirfenidone at concentrations of 500 μg / ml, 1000 μg / ml and 2500 μg / ml. In conclusion, AKF-PD is a more potent antiproliferative agent than pirfenidone in human astrocytes.
表3
人間の星状細胞におけるAKF−PD及びPEDの効果
Table 3
Effects of AKF-PD and PED on human astrocytes
*p<0.05 対 対照; **p<0.01 対 対照; ***p<0.001 対 対照
+p<0.05 対 AKF−PD; ++p<0.01 対 AKF−PD; +++p<0.001 対 AKF−PD
例4
1−(3’−フルオロフェニル)−5−メチル−2−(1H)−ピリドン及びピルフェニドンによるラットの肺の繊維芽細胞の増殖の抑制
* P <0.05 vs control; ** p <0.01 vs control; *** p <0.001 vs control
+ P <0.05 vs AKF-PD; ++ p <0.01 vs AKF-PD; +++ p <0.001 vs AKF-PD
Example 4
Inhibition of rat lung fibroblast proliferation by 1- (3′-fluorophenyl) -5-methyl-2- (1H) -pyridone and pirfenidone
細胞の増殖は、MTT分析によって測定された。10%の胎児の血清を備えたDMEMは、細胞の培養物の媒質として使用された。細胞は、懸濁液において調製され(1×105/ml)、且つ、懸濁液の100μLが、96個のウェルのプレートの各々のウェルへ移された。一度細胞が、プラスチックへ付着させられると、培養物は、血清の無い媒質に変化させられ、且つ、別の24時間の間に温置させられた。そして、血清の無い媒質は、吸引され、且つ、10%の血清の媒体における様々な濃度の1−(3’−フルオロフェニル)−5−メチル−2−(1H)−ピリドン(AKD−PD)又はピルフェニドン(PFD)は、各々の濃度について5個の複製を備えた各々のウェルの中へ追加された。細胞は、8、20、又は44時間の後の薬物の処置においてMTT(ウェル当たり10μL)で染色された。4時間の温置の後に、MTTを備えた媒質は、各々のウェルから吸引された。一百μLのMTTの溶媒が、15分の間に各々のウェルへ追加され、且つ、溶解させられたMTTは、570nmにおけるプレートの読取装置で測定された。 Cell proliferation was measured by MTT analysis. DMEM with 10% fetal serum was used as a medium for cell culture. Cells were prepared in suspension (1 × 10 5 / ml) and 100 μL of suspension was transferred to each well of a 96 well plate. Once the cells were attached to the plastic, the culture was changed to serum-free medium and incubated for another 24 hours. The serum-free medium is then aspirated and various concentrations of 1- (3′-fluorophenyl) -5-methyl-2- (1H) -pyridone (AKD-PD) in 10% serum medium Or pirfenidone (PFD) was added into each well with 5 replicates for each concentration. Cells were stained with MTT (10 μL per well) in drug treatment after 8, 20, or 44 hours. After 4 hours incubation, media with MTT was aspirated from each well. One hundred μL of MTT solvent was added to each well during 15 minutes, and the dissolved MTT was measured with a plate reader at 570 nm.
結果は、表4に示される。24時間の処置の後で、AKF−PDは、1000μg/mlと同程度の低いところにラットの肺の繊維芽細胞の増殖を抑制することができるであろうし、且つ、それは、2500μg/mlでピルフェニドンよりも抑制的なものであった。48時間の処置の後に、両方の化合物は、500μg/ml、1000μg/ml、及び2500μg/mlの薬物の濃度で効果を有するが、しかし、AKF−PDの抗増殖の効果は、500μg/ml及び1000μg/mlの濃度でピルフェニドンのものよりも強いものであった。結論において、AKF−PDは、ラットの肺の繊維芽細胞においてピルフェニドンよりも効能のある抗増殖剤である。 The results are shown in Table 4. After 24 hours of treatment, AKF-PD would be able to inhibit rat lung fibroblast proliferation as low as 1000 μg / ml, and that at 2500 μg / ml It was more suppressive than pirfenidone. After 48 hours of treatment, both compounds have effects at drug concentrations of 500 μg / ml, 1000 μg / ml, and 2500 μg / ml, but the anti-proliferative effect of AKF-PD is 500 μg / ml and It was stronger than that of pirfenidone at a concentration of 1000 μg / ml. In conclusion, AKF-PD is a more potent antiproliferative agent than pirfenidone in rat lung fibroblasts.
表4
ラットの肺の繊維芽細胞におけるAKF−PD及びPEDの効果
Table 4
Effects of AKF-PD and PED on rat lung fibroblasts
+p<0.05 対 AKF−PD; ++p<0.01 対 AKF−PD; +++p<0.001 対 AKF−PD
例5
1−(3’−フルオロフェニル)−5−メチル−2−(1H)−ピリドン及びピルフェニドンによる人間の皮膚の傷を形成する繊維芽細胞の増殖の抑制
細胞の増殖は、MTT分析によって測定された。10%の胎児の血清を備えたDMEMは、細胞の培養物の媒質として使用された。細胞は、懸濁液において調製され(1×105/ml)、且つ、懸濁液の100μLが、96個のウェルのプレートの各々のウェルへ移された。一度細胞が、プラスチックへ付着させられると、培養物は、血清の無い媒質に変化させられ、且つ、別の24時間の間に温置させられた。そして、血清の無い媒質は、吸引され、且つ、10%の血清の媒体における様々な濃度の1−(3’−フルオロフェニル)−5−メチル−2−(1H)−ピリドン(AKD−PD)又はピルフェニドン(PFD)は、各々の濃度について5個の複製を備えた各々のウェルの中へ追加された。細胞は、12、24、又は48時間の後の薬物の処置においてMTT(ウェル当たり10μL)で染色された。4時間の温置の後に、MTTを備えた媒質は、各々のウェルから吸引された。一百μLのMTTの溶媒が、15分の間に各々のウェルへ追加させられ、且つ、溶解させられたMTTは、570nmにおけるプレートの読取装置で測定された。
+ P <0.05 vs AKF-PD; ++ p <0.01 vs AKF-PD; +++ p <0.001 vs AKF-PD
Example 5
Inhibition of human skin wound fibroblast growth by 1- (3′-fluorophenyl) -5-methyl-2- (1H) -pyridone and pirfenidone Cell proliferation was measured by MTT analysis . DMEM with 10% fetal serum was used as a medium for cell culture. Cells were prepared in suspension (1 × 10 5 / ml) and 100 μL of suspension was transferred to each well of a 96 well plate. Once the cells were attached to the plastic, the culture was changed to serum-free medium and incubated for another 24 hours. The serum-free medium is then aspirated and various concentrations of 1- (3′-fluorophenyl) -5-methyl-2- (1H) -pyridone (AKD-PD) in 10% serum medium Or pirfenidone (PFD) was added into each well with 5 replicates for each concentration. Cells were stained with MTT (10 μL per well) in drug treatment after 12, 24, or 48 hours. After 4 hours incubation, media with MTT was aspirated from each well. One hundred μL of MTT solvent was added to each well for 15 minutes and the dissolved MTT was measured with a plate reader at 570 nm.
結果は、表5に示される。100μg/ml、500μg/ml、1000μg/ml、及び2500μg/mlの濃度での24時間の間における薬物の処置の後で、AKF−PD及びピルフェニドンの両方は、人間の皮膚の繊維芽細胞の成長を阻害することが可能なものであった;しかしながら、AKF−PDは、500μg/ml、1000μg/ml、及び2500μg/mlの濃度でピルフェニドンよりも効能のあるものであった。48時間の処置の後に、500μg/ml又は1000μg/mlのAKF−PDは、類似の濃度のピルフェニドンよりも多くの阻害を示した。結論において、AKF−PDは、人間の皮膚の繊維芽細胞においてピルフェニドンよりも効能のある抗増殖剤である。 The results are shown in Table 5. After treatment of the drug for 24 hours at concentrations of 100 μg / ml, 500 μg / ml, 1000 μg / ml, and 2500 μg / ml, both AKF-PD and pirfenidone develop fibroblast growth in human skin However, AKF-PD was more potent than pirfenidone at concentrations of 500 μg / ml, 1000 μg / ml, and 2500 μg / ml. After 48 hours of treatment, 500 μg / ml or 1000 μg / ml AKF-PD showed more inhibition than similar concentrations of pirfenidone. In conclusion, AKF-PD is a more potent anti-proliferative agent than pirfenidone in human skin fibroblasts.
表5
人間の皮膚の傷を形成する繊維芽細胞におけるAKF−PD及びPEDの効果
Table 5
Effects of AKF-PD and PED on fibroblasts forming wounds in human skin
*p<0.05 対 対照;**p<0.01 対 対照;***p<0.001 対 対照
+p<0.05 対 AKF−PD;++p<0.01 対 AKF−PD;+++p<0.001 対 AKF−PD
例6
1−(3’−フルオロフェニル)−5−メチル−2−(1H)−ピリドン及びピルフェニドンによる人間の腹膜の中皮の細胞の増殖の抑制
* P <0.05 vs control; ** p <0.01 vs control; *** p <0.001 vs control
+ P <0.05 vs AKF-PD; ++ p <0.01 vs AKF-PD; +++ p <0.001 vs AKF-PD
Example 6
Inhibition of human peritoneal mesothelial cell proliferation by 1- (3′-fluorophenyl) -5-methyl-2- (1H) -pyridone and pirfenidone
細胞の増殖は、MTT分析によって測定された。10%の胎児の血清を備えたDMEMは、細胞の培養物の媒質として使用された。細胞は、懸濁液において調製され(1×105/ml)、且つ、懸濁液の100μLが、96個のウェルのプレートの各々のウェルへ移された。一度細胞が、プラスチックへ付着させられると、培養物は、血清の無い媒質に変化させられ、且つ、別の24時間の間に温置させられた。そして、血清の無い媒質は、吸引され、且つ、10%の血清の媒体における様々な濃度の1−(3’−フルオロフェニル)−5−メチル−2−(1H)−ピリドン(AKD−PD)又はピルフェニドン(PFD)は、各々の濃度について5個の複製を備えた各々のウェルの中へ追加された。細胞は、12、24、又は48時間の後の薬物の処置においてMTT(ウェル当たり10μL)で染色された。4時間の温置の後に、MTTを備えた媒質は、各々のウェルから吸引された。一百μLのMTTの溶媒が、15分の間に各々のウェルへ追加され、且つ、溶解させられたMTTは、570nmにおけるプレートの読取装置で測定された。 Cell proliferation was measured by MTT analysis. DMEM with 10% fetal serum was used as a medium for cell culture. Cells were prepared in suspension (1 × 10 5 / ml) and 100 μL of suspension was transferred to each well of a 96 well plate. Once the cells were attached to the plastic, the culture was changed to serum-free medium and incubated for another 24 hours. The serum-free medium is then aspirated and various concentrations of 1- (3′-fluorophenyl) -5-methyl-2- (1H) -pyridone (AKD-PD) in 10% serum medium Or pirfenidone (PFD) was added into each well with 5 replicates for each concentration. Cells were stained with MTT (10 μL per well) in drug treatment after 12, 24, or 48 hours. After 4 hours incubation, media with MTT was aspirated from each well. One hundred μL of MTT solvent was added to each well during 15 minutes, and the dissolved MTT was measured with a plate reader at 570 nm.
結果は、表6に示される。500μg/ml、1000μg/ml、及び2500μg/mlの濃度での24時間の間における薬物の処置の後で、AKF−PD及びピルフェニドンの両方は、人間の腹膜の中皮の細胞の成長を阻害することが可能なものであった;しかしながら、AKF−PDは、1000μg/ml及び2500μg/mlの濃度でピルフェニドンよりも効能のあるものであった。48時間の処置の後に、1000μg/mlのAKF−PDは、類似の濃度のピルフェニドンよりも多くの阻害を示した。結論において、AKF−PDは、人間の腹膜の中皮の細胞においてピルフェニドンよりも効能のある抗増殖剤である。 The results are shown in Table 6. After 24 hours of drug treatment at concentrations of 500 μg / ml, 1000 μg / ml, and 2500 μg / ml, both AKF-PD and pirfenidone inhibit human peritoneal mesothelial cell growth However, AKF-PD was more potent than pirfenidone at concentrations of 1000 μg / ml and 2500 μg / ml. After 48 hours of treatment, 1000 μg / ml AKF-PD showed more inhibition than similar concentrations of pirfenidone. In conclusion, AKF-PD is a more potent anti-proliferative agent than pirfenidone in human peritoneal mesothelial cells.
表6
人間の腹膜の中皮の細胞においてAKF−PD及びPFDの効果
Table 6
Effects of AKF-PD and PFD on human peritoneal mesothelial cells
*p<0.05 対 対照; **p<0.01 対 対照; ***p<0.001 対 対照
+p<0.05 対 AKF−PD; ++p<0.01 対 AKF−PD; +++p<0.001 対 AKF−PD
例7
糸球体硬化症及び間質性の腎性の線維症における1−(3’−フルオロフェニル)−5−メチル−2−(1H)−ピリドン(AKF−PD)の効果
* P <0.05 vs control; ** p <0.01 vs control; *** p <0.001 vs control
+ P <0.05 vs AKF-PD; ++ p <0.01 vs AKF-PD; +++ p <0.001 vs AKF-PD
Example 7
Effect of 1- (3′-fluorophenyl) -5-methyl-2- (1H) -pyridone (AKF-PD) in glomerulosclerosis and interstitial renal fibrosis
ラットの糖尿病性の腎臓の疾患は、抗糸球体硬化症及び腎性の間質性の線維症を予防する際に1−(3’−フルオロフェニル)−5−メチル−2−(1H)−ピリドン(AKD−PD)の有効性を試験するためにストレプトゾトシン(STZ)によって誘発された。 The diabetic kidney disease of rats is 1- (3'-fluorophenyl) -5-methyl-2- (1H)-in preventing anti-glomerulosclerosis and renal interstitial fibrosis. Induced by streptozotocin (STZ) to test the efficacy of pyridone (AKD-PD).
八週間の老齢の雄のウィスターラット(180g〜220g)は、正常なもの、糖尿病性のネフローゼ、糖尿病性のネフローゼ/バルサルタン、又は糖尿病性のネフローゼ/AKF−PDとして無作為に群分けされた。糖尿病は、STZの55mg/kgの単一の腹腔内の注射によって誘発された。糖尿病性の健康状態は、24時間の後で、後に続く試験の結果:13.9mmol/Lの空腹時の血中のブドウ糖、16.7mmol/Lの無作為の血中のブドウ糖、及び陽性の尿中のブドウ糖によって、確認された。糖尿病性のラットが、4週の後で30mg/日よりも高い尿中のタンパク質のレベルを有するものであったとすれば、ラットのモデルは、糖尿病性のネフローゼについて確立された。 Eight-week-old male male Wistar rats (180-220 g) were randomly grouped as normal, diabetic nephrosis, diabetic nephrosis / valsartan, or diabetic nephrosis / AKF-PD. Diabetes was induced by a single intraperitoneal injection of 55 mg / kg of STZ. Diabetic health status is 24 hours later and the results of subsequent tests: 13.9 mmol / L fasting blood glucose, 16.7 mmol / L random blood glucose, and positive This was confirmed by glucose in the urine. If diabetic rats had urinary protein levels higher than 30 mg / day after 4 weeks, a rat model was established for diabetic nephrosis.
糖尿病性のネフローゼ/AKF−PDの群におけるラットは、500mg/kg/日のAKF−PDが経口的に給餌され、且つ、糖尿病性のネフローゼ/バルサルタンの群におけるラットは、30mg/kg/日のバルサルタンが給餌された。正常な生理食塩水が、糖尿病性のネフローゼの群におけるラットに給餌された。12週の薬物の処置の後に、全てのラットは、犠牲にされ、且つ、それらの腎臓は、病理学的な検査のために取り除かれた。糸球体及び腎臓の細管の間質の組織についての標準的な組織病理学的なスコアリングシステムについての参照文献は、:Radford et al.,IgA腎障害における腎臓の成果を予測すること。J.Am.Soc.Nephrol.8:199−207 (1997);Zhao et al.,プロマイシンの腎障害におけるアンギオテンシンII受容体の拮抗物質とアンギオテンシンを転換する酵素の阻害剤との間における腎臓の保護の効果及びそれらの可能性のある機構の比較。Chin.J.Mult.Organ Dis.Elderly 1:36−40(2002)である。 Rats in the diabetic nephrotic / AKF-PD group were orally fed 500 mg / kg / day AKF-PD and rats in the diabetic nephrotic / AKF-PD group were 30 mg / kg / day Valsartan was fed. Normal saline was fed to rats in the diabetic nephrotic group. After 12 weeks of drug treatment, all rats were sacrificed and their kidneys were removed for pathological examination. References for standard histopathological scoring systems for glomerular and renal tubule stromal tissue are: Radford et al. , Predicting renal outcome in IgA nephropathy. J. et al. Am. Soc. Nephrol. 8: 199-207 (1997); Zhao et al. Comparison of the protective effects of kidneys and their possible mechanisms between antagonists of angiotensin II receptor and inhibitors of enzymes that convert angiotensin in puromycin nephropathy. Chin. J. et al. Mult. Organ Dis. Elderly 1: 36-40 (2002).
腎臓の組織の顕微鏡の検査の結果は、表7に示される。いずれの処置無しの糖尿病性のネフローゼのラットと比較すると、AKF−PDで処置されたラットは、それらの糸球体及び腎臓の細管の間質の組織におけるより少ない損傷を示したが、AKF−PDが、糖尿病性の健康状態によって引き起こされた糸球体硬化症及び腎臓の細管の間質の線維症を有効に処置することもあることを示唆する。 The results of microscopic examination of the kidney tissue are shown in Table 7. Compared to diabetic nephrotic rats without any treatment, rats treated with AKF-PD showed less damage in their glomerular and renal tubule stromal tissues, but AKF-PD. Suggests that it may effectively treat glomerulosclerosis and fibrosis of renal tubules caused by diabetic health.
表7
異なる処置の群からの組織病理学的なスコア
Table 7
Histopathological scores from different treatment groups
例8
肺の線維症における1−(3’−フルオロフェニル)−5−メチル−2−(1H)−ピリドン(AKF−PD)の効果
Example 8
Effect of 1- (3′-fluorophenyl) -5-methyl-2- (1H) -pyridone (AKF-PD) on pulmonary fibrosis
ブレオマイシンで誘発されたラットの肺の線維症は、1−(3’−フルオロフェニル)−5−メチル−2−(1H)−ピリドン(AKD−PD)を試験するために選択される。雄のSprague−Dawleyラット(6−8週の老齢のもの、180〜220g)は、規則正しい条件の下で世話された。動物は、3個の群:偽の外科手術の群、モデル疾患の群、及び疾患/AKF−PDの群へと無作為に分割された。6mg/kg/4mlのブレオマイシンは、モデル疾患の群及び疾患/AKF−PDの群におけるラットの気管へとゆっくりと浸出された。同じ量の正常な生理食塩水は、偽の外科手術の群におけるラットの気管へと浸出された。 Bleomycin-induced rat lung fibrosis is selected to test 1- (3'-fluorophenyl) -5-methyl-2- (1H) -pyridone (AKD-PD). Male Sprague-Dawley rats (aged 6-8 weeks old, 180-220 g) were cared for under regular conditions. The animals were randomly divided into three groups: a sham surgical group, a model disease group, and a disease / AKF-PD group. 6 mg / kg / 4 ml bleomycin was slowly leached into the rat trachea in the model disease group and the disease / AKF-PD group. The same amount of normal saline was leached into the rat trachea in the sham surgical group.
500mg/kgのAKF−PDは、手術より先の2日から手術後の27日を通じて、毎日、疾患/AKF−PDの群におけるラットの腹部の中へと直接的に勢いよく流された。正常な生理食塩水は、疾患の群及び偽の外科手術の群の両方において全ての動物について使用された。動物は、27日後の外科手術に犠牲にされ、且つ、肺の組織が、病理学的な試料の調製について取り除かれた。各々のラットからのヘマトキシリン・エオシン染色された肺の組織は、繊維化の病変の頻度及び重症度を決定するために、顕微鏡の下で検査された。肺の組織の線維症の評価は、Szapiel et al.,裸の胸腺欠損のマウスにおけるブレオマイシンで誘発された間質性の肺の疾患。Am.Rev.Respir.Dis.120:893−9(1979)の方法に従って実行された。表8に示されたように、AKF−PDで処置されたラットは、疾患の群におけるものと比較すると、あまり重症なものではない繊維化の病変を示したが、AKF−PDが、肺の線維症の疾患を処置するための有効な薬剤であることもあることを示唆する。 500 mg / kg AKF-PD was flushed directly into the abdomen of rats in the disease / AKF-PD group daily from 2 days prior to surgery through 27 days after surgery. Normal saline was used for all animals in both the disease group and the sham surgical group. The animals were sacrificed after 27 days of surgery and lung tissue was removed for pathological sample preparation. Hematoxylin-eosin stained lung tissue from each rat was examined under a microscope to determine the frequency and severity of fibrotic lesions. Assessment of lung tissue fibrosis is described in Szapier et al. , Bleomycin-induced interstitial lung disease in naked athymic mice. Am. Rev. Respir. Dis. 120: 893-9 (1979). As shown in Table 8, rats treated with AKF-PD showed less severe fibrotic lesions compared to those in the disease group, but AKF-PD was It suggests that it may be an effective drug for treating fibrotic diseases.
表8
繊維化の病変の頻度及び重症度の比較
Table 8
Comparison of frequency and severity of fibrotic lesions
例9
肝臓の線維症における1−(3’−フルオロフェニル)−5−メチル−2−(1H)−ピリドン(AKF−PD)の効果
Example 9
Effect of 1- (3′-fluorophenyl) -5-methyl-2- (1H) -pyridone (AKF-PD) on liver fibrosis
Kun Ming(KM)マウスは、を住血吸虫症の肝臓の線維症を誘発させるために住血吸虫症のミラシジウムに感染させられた。四週から六週までの老齢の雄のKun Ming(KM)マウス(18−22g)は、健常なもの、感染させられたもの、感染させられたもの/ピクイトン(Pyquiton)、感染させられたもの/γ−インターフェロン、及び感染させられたもの/AKF−PDの群へと無作為に群分けされた。十匹の住血吸虫症のミラシジウムが、感染のために各々のマウスのシェービングされた腹部の皮膚に置かれた。感染させられたもの/ピクイトン、感染させられたもの/γ−インターフェロン、及び感染させられたもの/AKF−PDの群における感染後の八週のマウスは、4日の間における650mg/kgのピクイトンで処置することによって、消毒された。五百mg/kgのAKF−PDが、感染させられたもの/AKF−PDの群の消毒されたマウスへ、毎日、経口的に与えられた。消毒されたマウスには、毎日、(筋肉内の)50,000単位のγ−インターフェロンが与えられた。感染させられたもの/ピクイトン及び感染されられたものの群における消毒されたマウスには、薬物の投与の処置と同じ方式で、一日に一度、通常の生理食塩水が経口的に与えられた。薬物又は通常の生理食塩水の処置は、8週の間に連続させられた。全てのマウスは、薬物の処置を中断した後一週で、犠牲にされ、且つ、各々のマウスからの肝臓の左葉が、病理学的な検査のために取得された。 Kun Ming (KM) mice were infected with schistosomiasis miracidium to induce schistosomiasis liver fibrosis. Older male Kun Ming (KM) mice (18-22g) from 4 to 6 weeks were healthy, infected, infected / Pyquiton, infected / Randomly grouped into γ-interferon and infected / AKF-PD groups. Ten schistosomiasis miracidium were placed on the shaved abdominal skin of each mouse for infection. Eight weeks post-infection mice in the infected / picton, infected / γ-interferon, and infected / AKF-PD groups were 650 mg / kg picton for 4 days. It was disinfected by treating with. Five hundred mg / kg AKF-PD was given orally daily to disinfected mice in the infected / AKF-PD group. The sterilized mice were given 50,000 units (intramuscular) γ-interferon daily. Sterilized mice in the infected / picton and infected groups were given normal saline orally once a day in the same manner as the treatment of drug administration. Drug or normal saline treatment was continued for 8 weeks. All mice were sacrificed one week after discontinuing drug treatment, and the left lobe of the liver from each mouse was obtained for pathological examination.
肝臓の組織のHEで染色されたスライスの検査は、以下のように実行された。一般には、住血吸虫症のミラシジウムの感染の16週の後で、住血吸虫の卵子で誘発された小結節の面積は、肝臓の線維症の重症度に直接的に相関するであろう。従って、住血吸虫の卵子で誘発された小結節の面積は、高い分解能のカラーの病理学の図式の分析器(HPIAS−1000)を使用することで、測定された。密に詰め込まれた卵子を備えた5個の小結節の面積の総和及び軽く詰め込まれた卵子を備えた5個の小結節の面積の総和は、各々のスライスについて測定された。表9及び10に示されたように、AKF−PDで処置された動物は、処置無し(感染されたもののみ)又はピクイトンで処置された群のいずれかにおけるものよりも住血吸虫の卵子の小結節のより小さい面積(μm2)を有するものであった。これらの結果は、AKF−PDが、住血吸虫の肝臓の線維症を処置するための有効な薬理学的な薬剤であることもあることを示唆する。 Examination of HE-stained slices of liver tissue was performed as follows. In general, after 16 weeks of schistosomiasis Miracidium infection, the nodule area induced in schistosome eggs will directly correlate with the severity of liver fibrosis. Therefore, the area of nodules induced in schistosome eggs was measured using a high resolution color pathology schematic analyzer (HPIAS-1000). The total area of 5 nodules with tightly packed eggs and the total area of 5 nodules with lightly packed eggs were measured for each slice. As shown in Tables 9 and 10, animals treated with AKF-PD are less schistosome eggs than those in either the untreated (only infected) or the group treated with Picton. It had a smaller area (μm 2 ) of nodules. These results suggest that AKF-PD may be an effective pharmacological agent for treating schistosome liver fibrosis.
表9 住血吸虫の卵子で誘発された小結節の面積の比較 Table 9 Comparison of nodule area induced by schistosome eggs
表10 表9における群についてのP値
Table 10 P values for the groups in Table 9
例10
間質性のNaporoyl線維症のラットのモデルにおける1−(3’−フルオロフェニル)−5−メチル−2−(1H)−ピリドン(AKF−PD)の効果
Example 10
Effect of 1- (3′-fluorophenyl) -5-methyl-2- (1H) -pyridone (AKF-PD) in a rat model of interstitial Naporyl fibrosis
AKF−PDの抗線維症の効果は、単一の側の尿管の外科手術の結紮によって誘発された間質性のnaphorial線維症のSDのラットのモデルにおいて試験された。八週の老齢の雄のSDラット(180g〜220g)は、偽の外科手術の群、疾患のモデルの群、エナラプリル(10mg/kd/日)の群、及びAKF−PD(500mg/kg/日)の群へと無作為に分割された。無菌の条件の下で、疾患のモデルの群、エナラプリル及びAKF−PDにおける全ての動物は、左の側の尿管の結紮のために外科手術の手順を有するものであった。偽の外科手術の群の動物は、結紮のステップを除いて、同じ外科手術の手順を経験した。それぞれの薬物は、手順より先の一日から外科手術の手順の後の14日までエナラプリル及びAKF−PDの群におけるラットへ経口的に投与された。通常の生理食塩水が、疾患のモデル及び偽の外科手術のものの群におけるラットに類似の様式で投与された。動物は、外科手術の手順の後の14日に犠牲にされ、且つ、それらの左の腎臓は、病理学的な(HEで染色する)検査のために、取り除かれた。間質性の区画についての組織学的なスコアリングは、Radfordの方法(Radford et al.,Predicting renal outcome in IgA nephropathy. J.Am.Soc.Nephrol.8:199−207(1997))に従って行われた。表11に示されたように、AKF−PDで処置されたラットは、疾患のモデル及びエナラプリルの群におけるものに対して比較することで、間質性の組織における低減された病変を示したが、AKF−PDが、間質性の腎性の線維症についての有効な薬物であることもあることを示唆するものである。 The anti-fibrotic effect of AKF-PD was tested in a rat model of SD with interstitial naforal fibrosis induced by single-sided ureteral surgical ligation. Eight week old male SD rats (180g-220g) were divided into sham surgical group, disease model group, enalapril (10 mg / kd / day) group, and AKF-PD (500 mg / kg / day). ) Was randomly divided into groups. Under sterile conditions, all animals in the disease model group, enalapril and AKF-PD had surgical procedures for ligation of the left ureter. Animals in the sham surgical group experienced the same surgical procedure except for the ligation step. Each drug was administered orally to rats in the enalapril and AKF-PD groups from one day prior to the procedure to 14 days after the surgical procedure. Normal saline was administered in a similar manner to rats in groups of disease models and sham surgical ones. The animals were sacrificed 14 days after the surgical procedure, and their left kidneys were removed for pathological (HE staining) examination. Histological scoring for the interstitial compartment was performed according to the method of Radford (Radford et al., Predicting renal outcome in IgA nephropathy. J. Am. Soc. Nephrol. 8: 199-207 (1997)). It was broken. As shown in Table 11, although rats treated with AKF-PD showed reduced lesions in interstitial tissue when compared to those in the disease model and enalapril group. This suggests that AKF-PD may be an effective drug for interstitial renal fibrosis.
表11
間質性の区画についての組織学的なスコアの比較
Table 11
Comparison of histological scores for interstitial compartments
例11
1−(3−フルオロフェニル)−5−メチル−2(1H)−ピリドン(AKF−PD)及びピルフェニドンの急性の毒性の比較
Example 11
Comparison of acute toxicity of 1- (3-fluorophenyl) -5-methyl-2 (1H) -pyridone (AKF-PD) and pirfenidone
18g−22gの間の重量である雄及び雌のKun Ming(KM)マウスは、Hsiang−Ya Medical College、the Central South Universityの動物の施設から獲得された。五十匹のKun Mingマウスは、各々の群について5匹の雄及び5匹の雌のマウスを備えた、5個の群へと無作為に割り当てられた。動物は、薬物の処置(AKF−PD又はピルフェニドンのいずれか)を開始する前に通常の水の供給と共に断食すること経験した。薬物は、胃管栄養法によって経口的に投与された。液体の薬物の体積は、20ml/kgの体重のものであった。AKF−PDが投与されたものについての薬用量の範囲は、1071mg/kgから6000mg/kgまでであった。二つの隣接した用量の間における薬用量の差異は、1:0.65(ある用量 対 次により低い用量)であった。全ての動物は、日常的な条件の下で維持された。薬物の処置の後の14日以内の急性の毒性の反応及び死亡は、記録された。死体解剖は、全ての死亡した動物について行われ、且つ、目視の検査が、全ての器官において行われた。 Male and female Kun Ming (KM) mice weighing between 18g-22g were obtained from the animal facility of Hsiang-Ya Medical College, the Central South University. Fifty Kun Ming mice were randomly assigned to 5 groups with 5 males and 5 female mice for each group. The animals experienced fasting with a regular water supply prior to initiating drug treatment (either AKF-PD or pirfenidone). The drug was administered orally by gavage. The liquid drug volume was 20 ml / kg body weight. The dose range for those administered AKF-PD was 1071 mg / kg to 6000 mg / kg. The dose difference between two adjacent doses was 1: 0.65 (some dose vs. the next lower dose). All animals were maintained under routine conditions. Acute toxic reactions and death within 14 days after drug treatment were recorded. Necropsy was performed on all dead animals, and visual inspection was performed on all organs.
LD50は、Blissの方法に従って計算された。1−(3−フルオロフェニル)−5−メチル−2(1H)−ピリドンについての急性の毒性LD50は、2402.70−−3695.73mg/kgの95%の信頼限界で、2979.89mg/kgであった(表12)。ピルフェニドンについてのLD50は、550.9−−1656.7mg/kgの95%の信頼限界で、955.4mg/kgであった(表13)。表13の結果は、文献に報告されたもの997.7mg/kg(米国特許第5,310,562号明細書)及び1112 mg/kg(Pharmaceutical Care and Research 5:4823(2005)):に非常に近いものである。これらの結果は、AKF−PDについての毒性は、ピルフェニドンのものに比較されると、3倍未満である(2978 対 955)ことを示唆する。 The LD 50 was calculated according to the Bliss method. The acute toxicity LD50 for 1- (3-fluorophenyl) -5-methyl-2 (1H) -pyridone is 2979.89 mg / kg with a 95% confidence limit of 240.70--3695.73 mg / kg. (Table 12). The LD 50 for pirfenidone was 955.4 mg / kg with a 95% confidence limit of 550.9-1656.7 mg / kg (Table 13). The results in Table 13 are very similar to those reported in the literature: 997.7 mg / kg (US Pat. No. 5,310,562) and 1112 mg / kg (Pharmaceutical Care and Research 5: 4823 (2005)): It is close. These results suggest that the toxicity for AKF-PD is less than 3-fold (2978 vs. 955) when compared to that of pirfenidone.
表12
5−メチル−1−(3−フルオロフェニル)−2(1H)−ピリドンのLD50
Table 12
LD 50 of 5-methyl-1- (3-fluorophenyl) -2 (1H) -pyridone
表13
ピルフェニドンのLD50
Table 13
Pirfenidone LD 50
Claims (10)
を有する、化合物、5−メチル−1−(置換されたフェニル)−2(1H)−ピリドン類の使用であって、n=1のとき、置換R=F、Cl、Br、I、ニトロ、アルキル基、アルコキシ基、ハロゲン化されたアルキル基である;n=2のとき、置換R=F、Cl、Br、I、アルキル基、アルコキシ基、ハロゲン化されたアルキル基である、使用。 The general structural formula (I) in the manufacture of a medicament for treating fibrosis of an organ or tissue,
Use of the compound, 5-methyl-1- (substituted phenyl) -2 (1H) -pyridones, when n = 1, the substitution R = F, Cl, Br, I, nitro, Use wherein alkyl group, alkoxy group, halogenated alkyl group; when n = 2, substituted R = F, Cl, Br, I, alkyl group, alkoxy group, halogenated alkyl group.
n=1,R=Brのとき、前記化合物は、1−(2−ブロモフェニル)−5−メチル−2−(1H)−ピリドン、1−(3−ブロモフェニル)−5−メチル−2−(1H)−ピリドン、1−(4−ブロモフェニル)−5−メチル−2−(1H)−ピリドンである:
n=1、R=Fのとき、前記化合物は、1−(2−フルオロフェニル)−5−メチル−2−(1H)−ピリドン、1−(3−フルオロフェニル)−5−メチル−2−(1H)−ピリドン、1−(4−フルオロフェニル)−5−メチル−2−(1H)−ピリドンである:
n=1、R=Iのとき、前記化合物は、1−(2−ヨードフェニル)−5−メチル−2−(1H)−ピリドン、1−(3−ヨードフェニル)−5−メチル−2−(1H)−ピリドン、1−(4−ヨードフェニル)−5−メチル−2−(1H)−ピリドンである:
n=2、R=F又はBr又はClのとき、前記化合物は、1−(2,3−ジブロモフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,4−ジブロモフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,5−ジブロモフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,6−ジブロモフェニル)−5−メチル−2−(1H)−ピリドン、1−(3,4−ジブロモフェニル)−5−メチル−2−(1H)−ピリドン、1−(3,5−ジブロモフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,3−ジクロロフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,4−ジクロロフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,5−ジクロロフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,6−ジクロロフェニル)−5−メチル−2−(1H)−ピリドン、1−(3,5−ジクロロフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,3−ジフルオロフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,4−ジフルオロフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,5−ジフルオロフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,6−ジフルオロフェニル)−5−メチル−2−(1H)−ピリドン、1−(3,5−ジフルオロフェニル)−5−メチル−2−(1H)−ピリドンである:
n=1又は2、R=トリフルオロメチルのとき、前記化合物は、5−メチル−1−(2−トリフルオロメチルフェニル)−2−(1H)−ピリドン、5−メチル−1−(4−トリフルオロメチルフェニル)−2−(1H)−ピリドン、5−メチル−1−(2,3−ビス−トリフルオロメチルフェニル)−2−(1H)−ピリドン、5−メチル−1−(2,4−ビス−トリフルオロメチルフェニル)−2−(1H)−ピリドン、5−メチル−1−(2,5−ビス−トリフルオロメチルフェニル)−2−(1H)−ピリドン、5−メチル−1−(2,6−ビス−トリフルオロメチルフェニル)−2−(1H)−ピリドン、5−メチル−1−(3,4−ビス−トリフルオロメチルフェニル)−2−(1H)−ピリドン、及び5−メチル−1−(3,5−ビス−トリフルオロメチルフェニル)−2−(1H)−ピリドンである:
n=1又は2及びR=メチルのとき、前記化合物は、5−メチル−1−(2−メチルフェニル)−2−(1H)−ピリドン、5−メチル−1−(3−メチルフェニル)−2−(1H)−ピリドン、1−(2,3−ジメチルフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,4−ジメチルフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,5−ジメチルフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,6−ジメチルフェニル)−5−メチル−2−(1H)−ピリドン、1−(3,4−ジメチルフェニル)−5−メチル−2−(1H)−ピリドン、及び1−(3,5−ジメチルフェニル)−5−メチル−2−(1H)−ピリドンである:
n=1又は2、R=メトキシのとき、前記化合物は、5−メチル−1−(2−メトキシフェニル)−2−(1H)−ピリドン、5−メチル−1−(3−メトキシフェニル)−2−(1H)−ピリドン、1−(2,3−ジメトキシフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,4−ジメトキシフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,5−ジメトキシフェニル)−5−メチル−2−(1H)−ピリドン、1−(2,6−ジメトキシフェニル)−5−メチル−2−(1H)−ピリドン、1−(3,4−ジメトキシフェニル)−5−メチル−2−(1H)−ピリドン、及び1−(3,5−ジメトキシフェニル)−5−メチル−2−(1H)−ピリドンである:
を有する、請求項2に記載の使用。 The compound, 5-methyl-1- (substituted phenyl) -2 (1H) -pyridones (general structural formula I), has the following features:
When n = 1 and R = Br, the compound is 1- (2-bromophenyl) -5-methyl-2- (1H) -pyridone, 1- (3-bromophenyl) -5-methyl-2- (1H) -pyridone, 1- (4-bromophenyl) -5-methyl-2- (1H) -pyridone:
When n = 1 and R = F, the compound is 1- (2-fluorophenyl) -5-methyl-2- (1H) -pyridone, 1- (3-fluorophenyl) -5-methyl-2- (1H) -pyridone, 1- (4-fluorophenyl) -5-methyl-2- (1H) -pyridone:
When n = 1 and R = I, the compound is 1- (2-iodophenyl) -5-methyl-2- (1H) -pyridone, 1- (3-iodophenyl) -5-methyl-2- (1H) -pyridone, 1- (4-iodophenyl) -5-methyl-2- (1H) -pyridone:
When n = 2, R = F or Br or Cl, the compound is 1- (2,3-dibromophenyl) -5-methyl-2- (1H) -pyridone, 1- (2,4-dibromophenyl) ) -5-methyl-2- (1H) -pyridone, 1- (2,5-dibromophenyl) -5-methyl-2- (1H) -pyridone, 1- (2,6-dibromophenyl) -5 Methyl-2- (1H) -pyridone, 1- (3,4-dibromophenyl) -5-methyl-2- (1H) -pyridone, 1- (3,5-dibromophenyl) -5-methyl-2- (1H) -pyridone, 1- (2,3-dichlorophenyl) -5-methyl-2- (1H) -pyridone, 1- (2,4-dichlorophenyl) -5-methyl-2- (1H) -pyridone, 1- (2,5-dichlorophenyl) -5-methyl-2- (1 ) -Pyridone, 1- (2,6-dichlorophenyl) -5-methyl-2- (1H) -pyridone, 1- (3,5-dichlorophenyl) -5-methyl-2- (1H) -pyridone, 1- (2,3-difluorophenyl) -5-methyl-2- (1H) -pyridone, 1- (2,4-difluorophenyl) -5-methyl-2- (1H) -pyridone, 1- (2,5 -Difluorophenyl) -5-methyl-2- (1H) -pyridone, 1- (2,6-difluorophenyl) -5-methyl-2- (1H) -pyridone, 1- (3,5-difluorophenyl) -5-methyl-2- (1H) -pyridone:
When n = 1 or 2, R = trifluoromethyl, the compound is 5-methyl-1- (2-trifluoromethylphenyl) -2- (1H) -pyridone, 5-methyl-1- (4- Trifluoromethylphenyl) -2- (1H) -pyridone, 5-methyl-1- (2,3-bis-trifluoromethylphenyl) -2- (1H) -pyridone, 5-methyl-1- (2, 4-bis-trifluoromethylphenyl) -2- (1H) -pyridone, 5-methyl-1- (2,5-bis-trifluoromethylphenyl) -2- (1H) -pyridone, 5-methyl-1 -(2,6-bis-trifluoromethylphenyl) -2- (1H) -pyridone, 5-methyl-1- (3,4-bis-trifluoromethylphenyl) -2- (1H) -pyridone, and 5-Methyl-1- (3 - bis - trifluoromethyl phenyl) -2- (1H) - it is pyridone:
When n = 1 or 2 and R = methyl, the compound is 5-methyl-1- (2-methylphenyl) -2- (1H) -pyridone, 5-methyl-1- (3-methylphenyl)- 2- (1H) -pyridone, 1- (2,3-dimethylphenyl) -5-methyl-2- (1H) -pyridone, 1- (2,4-dimethylphenyl) -5-methyl-2- (1H ) -Pyridone, 1- (2,5-dimethylphenyl) -5-methyl-2- (1H) -pyridone, 1- (2,6-dimethylphenyl) -5-methyl-2- (1H) -pyridone, 1- (3,4-dimethylphenyl) -5-methyl-2- (1H) -pyridone and 1- (3,5-dimethylphenyl) -5-methyl-2- (1H) -pyridone:
When n = 1 or 2, R = methoxy, the compound is 5-methyl-1- (2-methoxyphenyl) -2- (1H) -pyridone, 5-methyl-1- (3-methoxyphenyl)- 2- (1H) -pyridone, 1- (2,3-dimethoxyphenyl) -5-methyl-2- (1H) -pyridone, 1- (2,4-dimethoxyphenyl) -5-methyl-2- (1H) ) -Pyridone, 1- (2,5-dimethoxyphenyl) -5-methyl-2- (1H) -pyridone, 1- (2,6-dimethoxyphenyl) -5-methyl-2- (1H) -pyridone, 1- (3,4-dimethoxyphenyl) -5-methyl-2- (1H) -pyridone and 1- (3,5-dimethoxyphenyl) -5-methyl-2- (1H) -pyridone:
Use according to claim 2, wherein
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PCT/CN2006/000651 WO2006108354A1 (en) | 2005-04-13 | 2006-04-11 | 1-(substituted phenyl)-5- methyl- 2 - (1h) pyridone in the manufacture of medicaments for treating fibrosis in organs or tissues |
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JP2008505716A Pending JP2008535871A (en) | 2005-04-13 | 2006-04-11 | 5-Methyl-1- (substituted phenyl) -2- (1H) -pyridone in the manufacture of a medicament for treating fibrosis in an organ or tissue |
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US (3) | US20090005424A9 (en) |
EP (1) | EP1878428A4 (en) |
JP (1) | JP2008535871A (en) |
KR (1) | KR20080018857A (en) |
CN (2) | CN1846699A (en) |
AU (1) | AU2006233433A1 (en) |
CA (1) | CA2603763A1 (en) |
RU (1) | RU2007141892A (en) |
TW (1) | TW200808315A (en) |
WO (1) | WO2006108354A1 (en) |
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- 2005-04-13 CN CNA2005100314457A patent/CN1846699A/en active Pending
-
2006
- 2006-04-11 CA CA002603763A patent/CA2603763A1/en not_active Abandoned
- 2006-04-11 CN CN2006800002161A patent/CN1953749B/en active Active
- 2006-04-11 AU AU2006233433A patent/AU2006233433A1/en not_active Abandoned
- 2006-04-11 WO PCT/CN2006/000651 patent/WO2006108354A1/en active Application Filing
- 2006-04-11 RU RU2007141892/15A patent/RU2007141892A/en not_active Application Discontinuation
- 2006-04-11 JP JP2008505716A patent/JP2008535871A/en active Pending
- 2006-04-11 EP EP06722303A patent/EP1878428A4/en not_active Withdrawn
- 2006-04-11 KR KR1020077018590A patent/KR20080018857A/en not_active Application Discontinuation
- 2006-08-04 TW TW095128659A patent/TW200808315A/en unknown
-
2007
- 2007-05-01 US US11/742,664 patent/US20090005424A9/en not_active Abandoned
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2008
- 2008-09-04 US US12/204,629 patent/US20080319027A1/en not_active Abandoned
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2009
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US8903573B2 (en) | 2006-03-20 | 2014-12-02 | General Electric Company | Method and computer software code for determining a mission plan for a powered system when a desired mission parameter appears unobtainable |
US9156477B2 (en) | 2006-03-20 | 2015-10-13 | General Electric Company | Control system and method for remotely isolating powered units in a vehicle system |
US9733625B2 (en) | 2006-03-20 | 2017-08-15 | General Electric Company | Trip optimization system and method for a train |
US10308265B2 (en) | 2006-03-20 | 2019-06-04 | Ge Global Sourcing Llc | Vehicle control system and method |
US10569792B2 (en) | 2006-03-20 | 2020-02-25 | General Electric Company | Vehicle control system and method |
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JP2016540800A (en) * | 2013-12-19 | 2016-12-28 | サンシャイン・レイク・ファーマ・カンパニー・リミテッドSunshine Lake Pharma Co.,Ltd. | Nitrogen heterocyclic derivatives and their applications in medicine |
Also Published As
Publication number | Publication date |
---|---|
KR20080018857A (en) | 2008-02-28 |
CN1953749B (en) | 2010-04-14 |
CN1953749A (en) | 2007-04-25 |
CA2603763A1 (en) | 2006-10-19 |
AU2006233433A1 (en) | 2006-10-19 |
WO2006108354A1 (en) | 2006-10-19 |
US20090005424A9 (en) | 2009-01-01 |
US20080319027A1 (en) | 2008-12-25 |
US20090258911A1 (en) | 2009-10-15 |
US20070203203A1 (en) | 2007-08-30 |
RU2007141892A (en) | 2009-05-20 |
EP1878428A1 (en) | 2008-01-16 |
TW200808315A (en) | 2008-02-16 |
EP1878428A4 (en) | 2008-09-03 |
CN1846699A (en) | 2006-10-18 |
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